Genetic alterations affecting the elastin gene cause the vascular features of Williams syndrome and isolated supravalvular aortic stenosis (SVAS). Previous research has shown that humans with elastin- mediated disease display a range in severity of their vascular phenotypes;from life-threatening stenoses and hypertension to no appreciable cardiovascular features at all. The goal of this application is to identify genes that control the severity of these vascular phenotypes. The Eln mouse provides a good model system through which to study this variation. Preliminary studies performed by this laboratory show alterations in vascular phenotype when the Eln mouse is out-crossed from the parental C57 strain into different inbred backgrounds. Biochemical analyses of the aortas of those animals reveal that differences in the quantity of elastin deposited by each strain are not responsible for variation in disease severity. Consequently, other elastin independent modifiers of the elastin haploinsufficiency phenotype must be present that alter the risk for severe vascular disease. Analysis of F1 animals has identified one genetic background with more severe vascular phenotypes (C57x129 Eln) and one that is protected from pathology associated with elastin haploinsufficiency (C57xDBA Eln). Based on these preliminary data, we established the following aims: 1) We will map genetic loci that modify the phenotypic expression of elastin haplosinsufficiency using F2 crosses and SNP genotyping with QTL analysis. 2) We will narrow the loci and number of potential candidates that affect the expression of elastin mediated vascular disease using a combination of high density mapping techniques and allele specific analysis of RNASeq. Identification of elastin indpendent modifiers of vascular disease is important as it may represent potential targets for new therapies aimed a treating/preventing cardiovascular disease in individuals with Williams's syndrome/SVAS. PUBLIC HEALTH RELEVANCE: This project seeks to identify genes involved with modifying the cardiovascular effect of elastin deficiency. The findings are likely to provide insight into vascular development and cardiovascular function.